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"Biosensing is a hot research trend, especially in China where the technology is important to every major aspect of our daily lives," says Xianting Ding, Ph.D., School of Biomedical Engineering, Institute for Personalized Medicine, Shanghai Jiao Tong University. "Now we see it starting to make a difference in all parts of the world, and in disciplines as diverse as disease diagnosis, environmental monitoring, food engineering and drug discovery."

In China, biosensing has many potential applications, Ding observes. "We are always worried whether our milk is safe to drink, so we need biosensing technology to tell whether it contains any toxins. Before we exercise outdoors, we want to know if the air quality is good enough—whether there are particulates we want to avoid. Similarly, before we swim in a particular body of water or eat fish that are caught there, we need biosensing to determine whether that water is safe. So biosensing really touches upon everything we are faced with in everyday life."

Power of a Drop of Blood

When Ding was working on his Ph.D. in mechanical engineering in the lab of Chih-Ming Ho, Ph.D., at the University of California, Los Angeles (UCLA), "we were trained to fabricate tiny sensors that can detect antibodies in just one or two drops of human blood," he recalls. "When I came back to China, I realized the potential of the technology in the real world. No one there wants to donate five millimeters of blood just to get one test done. I thought, 'what if we could get everything done with a couple of drops of blood or urine or saliva? That could change everything.'"

Currently, the Ding lab is working on doing just that: developing biosensors that can detect multiple targets—proteins, mRNA, DNA, chemical compounds—simultaneously. "When most people talk about personalized or precision medicine, they're referring to targeting differences at the genome level," Ding says. "But personalization also happens at the cellular level, at the tissue level, at many different levels beyond the genome. Our group is fabricating a platform that combines all these different levels into a single chip that can detect concentrations of multiple substances, all from a drop or two of blood. Personalization would be based not on just one level of a particular protein, for example, but rather on the combination of proteins and other substances detected from an individual." The work holds promise for the early detection of cancer and many other diseases, as well as the optimization of drug therapies.

Currently, the group is trying to improve the platform's sensitivity—that is, improving the ability to detect proteins and other substances that are found in very low concentrations in blood. Then they will focus on two other important characteristics for biosensors: low power demand and low cost. Several articles in the JALA special issue address similar issues.

Progress in Paper-Based Point-of-Care

The review entitled "Paper-Based Systems for Point-of-Care Biosensing" provides a summary of improvements underway in the design and sensitivity of these diagnostic testing devices. "Both concepts—paper-based and point-of-care—are significant," Ding says. Point-of-care is key because it means the equipment is accessible to clinicians and the general public. "Instead of sending test results to a big lab for interpretation by highly trained technicians, we are now at a point where local hospitals or doctors can conduct and interpret some of the diagnostic tests themselves."

Paper-based sensors are especially valuable because "there are no requirements for external pumping to push liquids into the channels, which saves a lot of power," Ding says. "The other major benefit is low cost. If we can fabricate a paper-based sensor that can relatively efficiently tell whether a person is infected with HIV or malaria, for example, it will be of great benefit to people living in rural China, India, South Africa and other developing nations." That perspective is shared by Patrick Beattie, 2014 SLAS Innovation Award winner and Skoll Scholar at Skoll Centre for Social Entrepreneurship, Said Business School, University of Oxford. Beattie described his award-winning work with paper-based microfluidic diagnostics in a recent SLAS ELN feature article (free to all) and on-demand webinar (free to SLAS members).

In their JALA review, coauthors Sherine F. Chung, Samantha K. L. Cheng and Daniel T. Kamei of the UCLA Department of Engineering cover the history of paper-based diagnostics and more recent innovations, such as 3D microfluidic paper-based analytical devices (μPADs), chemical patterning (treating paper with chemicals and reagents to give the paper device enhanced functionality) and origami paper devices (using origami-folding approaches to build a 3D diagnostic device from a single piece of paper).

Combining Microarray and Label-Free Technologies

The JALA review entitled "Use of Microarrays as a High-Throughput Platform for Label-Free Biosensing" also highlights two important concepts of interest, Ding observes. "Label-free technologies are huge right now, particularly in China's biosensing research community," he says. That's because labeling, or staining, a small group of cells with biomarkers may change the properties of the cells when they go through the flow cytometry and sorting process, thereby confounding results. Other problems include the heterogeneity of biomolecules, which leads to variable labeling efficiency from one molecule to another, and the fact that labeling biomolecules "is very laborious and expensive," according to review article author Yung-Shin Sun of Fu-Jen Catholic University, Taiwan.

"Eliminating staining will take biosensing technology to a whole new level," Ding says. Similarly, combining label-free technology with microarray technology "will significantly expand biosensing's potential. If you have an array of bacteria on a single chip, you can test multiple biomolecular interactions in parallel, instead of doing similar experiments over and over. That's efficient and labor-saving."

Platforms that combine microarrays and label-free biosensors will be useful for scientists working in "genomics, proteomics, glycomics, drug screenings, and even areas of food and environmental analysis," Sun writes. Although research on such platforms—specifically, combining microarrays with surface plasmon resonance imaging (SPRi) and oblique-incidence reflectivity difference (OI-RD) microscopes—is ongoing, there is room for improvement. He pinpoints several key issues: Sensitivity needs to be improved, especially for small clinical samples; faster imaging is needed to optimize the efficiency of such platforms for screening; immobilization of a variety of biomolecules requires a knowledge of chemistry not everyone has, because the probe molecules and/or the microarray substrates need to be modified; and the probes to be screened may consist of many unknown molecules, so an additional technology, such as mass spectrometry, is needed to identify everything that has been captured on the surface.

Even given the need for improvements, "...using microarrays in label-free biosensors has become a current trend in developing high-throughput screening platforms, and this will eventually lead us to a new era of the '-omics,'" Sun concludes.

Novel Biosensing Strategies

The original research papers in the JALA special issue demonstrate efforts to use and refine biosensing technology in innovative ways, in areas such as early disease detection, agricultural crop safety and laboratory research. Ding discusses three examples.

Certain low-abundance nucleic acids "somehow serve as biomarkers themselves, particularly for disease diagnosis," Ding observes. "Some patients with abnormal levels of these nucleic acids may already show symptoms. For others, minor shifts in nucleic acid concentration may be an early indication of disease."

For example, Lam, Chen and Chen note that seven signature messenger RNAs in saliva are elevated in the presence of oral cancer, while concentrations of microRNAs—small regulatory RNAs present in the bloodstream due to cancer—can help in cancer classification and prognostication. Chromosomal markers with species-specific sequences can be used to differentiate pathogenic strains; this has relevance for both food safety and bioterrorism threats. The coauthors conclude that "effective detection and identification [of nucleic acids in low abundance] affect many aspects of our lives, including food safety, water contamination and diseases."

InPlanta Microsphere.Ding says he's "never seen anything like" the work of Jessica T. Wen, Carlos Castro and Hideaki Tsutsui of the University of California, Riverside in their paper, "In Planta Microsphere-Based Lateral Flow Leaf Biosensor in Maize." The team has developed a lateral flow detection technology directly integrated into a maize leaf. "In effect, they are building biosensing right into the leaves of living plants by using the naturally occurring microchannels as an infrastructure. That allows them to bypass the whole biosensor fabrication step, which makes this approach incredibly inexpensive, and also green, since it does not require cutting and squeezing plants to obtain liquids for testing." Key to the technology are microspheres conjugated with analyte-specific capture antibodies that are noninvasively injected into the leaves, and that capture and detect analytes in a concentration-specific way.

The authors of the study observe that maize is one of the most widely grown staple crops globally, and that in developing regions of sub-Saharan Africa and Mesoamerica, up to 73% of total maize production is used as a food source. However, maize crops incur significant losses both pre- and post-harvest to biotic stresses such as viruses, fungi, bacteria and other pathogens. Rapid detection of specific biotic stresses "is critically important" to protect maize and other staple food crops, particularly in small farms in developing countries, according to the authors. "This in planta lateral flow biosensor is the first of its kind and is expected to provide a low-cost and user-friendly detection method for biotic stresses in the field."

Petrijet Platform. Most of the original research in the special issue involves scientific studies and experiments. But "PetriJet Platform Technology: An Automated Platform for Culture Dish Handling and Monitoring of the Contents" is "particularly interesting because it involves the development of a product that can help laboratory researchers," Ding says. "In our lab, we handle Petri dishes with our hands, and when we are running many experiments in parallel, it's a pain to handle multiple dishes ourselves. This platform would enable us to deal with that issue."

The authors of the report, Mathias Vogel, Elke Boschke, Thomas Bley and Felix Lenk, Technische Universität Dresden, Germany, note that automated laboratory systems often are not practical for small- and mid-sized laboratories because of the size of the required equipment. They developed the new system, which automatically obtains an image of every sealed culture dish that is processed and provides the user with various parameters related to the cultivated sample, to help fill that gap. The benchtop device, which will facilitate biosensor and other research, is movable by one person, weighs no more than 30 kg (66 pounds), can be placed under a laminar flow cabinet, has surfaces that can be disinfected and includes a wireless control mechanism.

"Most automated handling products handle microplates, rather than culture dishes," Ding says. "With a system like this, we may be able to create a whole new pipeline of experiments in culture dishes."

Jobs and Collaboration Opportunities

The Chinese government is actively supporting research into biosensing, and a number of start-up companies focusing on the technologies have emerged over the past couple of years, according to Ding. "People working in biosensing right now, no matter where they're from, can easily find jobs in Asia," he says. "It's an important research focus not only in China, but also in Singapore, Hong Kong, Japan and South Korea. Companies are eager to hire people that have expertise in designing, fabricating or working with biosensors to meet the demand of the growing market.

"The articles in the JALA Special Issue on biosensing represent research underway in Asia, as well as in Europe and the United States," Ding continues. "I hope the issue will promote bonding among these research communities and collaborations going forward."

Learn More in this August 2015 JALA Special Issue

The JALA Special Issue on New Developments in Biosensing Technologies features five review articles, 10 original research reports and two technology briefs on promising new achievements in the thriving field of biosensors. Highlights include advances in point-of-care biosensing and portable biosensors; new technologies to facilitate drug discovery; and novel methods of identifying, optimizing and monitoring molecules of interest.

The special issue is part of the SLAS commitment to improving access to information for health professionals, scientists and policy makers around the world, according to SLAS President Dean Ho. SLAS participates in the Health InterNetwork Access to Research Initiative (HINARI) by providing free or low-cost access to JALA and JBS to more than 6,000 publicly funded non-profit institutions in over 100 countries and territories in the developing world. In addition, deeply discounted membership rates make it easier for life sciences R&D professionals in emerging economies to join SLAS and enjoy full access to its many programs, products, services and events.

August 7, 2015

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